Project Summary/Abstract The prevalence of pulmonary infections caused by nontuberculous mycobacteria (NTM) is increasing worldwide, and among them, chronic pulmonary disease caused by Mycobacterium abscessus complex (MABC) is the most difficult to manage. A common cause of opportunistic lung infections in patients with cystic fibrosis and other pre- existing lung diseases, MABC organisms are naturally resistant to almost all known antibiotics; there is no known curative treatment regimen for chronic MABC lung disease, and thus the prognosis is poor. The two major ob- stacles to improving treatment of MABC pulmonary disease are first the lack of research to discover new drugs effective against MABC, and second the lack of validated preclinical models of long-term chemotherapy that could support evaluation of potentially curative treatment regimens. The research described in this proposal contributes to addressing both of these fundamental issues. By accessing novel antimycobacterial compounds already in development for tuberculosis treatment (through partnership with the Global Alliance for TB Drug Development), the bactericidal activity of new combination drug regimens will be evaluated in a mouse model of acute MABC infection. Data obtained from this work has immediate translational potential and could rapidly provide new treatment options for patients with MABC pulmonary disease. However, as short-term treatment studies cannot accurately predict the long-term curative potential of a regimen, a series of novel infection strat- egies will be assessed for development of a mouse model of chronic MABC pulmonary disease. Development of a reproducible mouse model of chronic MABC lung disease will better preclinical-to-clinical translation of po- tentially curative treatment regimens. Overall, the work in this proposal is expected to produce new treatment regimens for patients with MABC pulmonary disease and new tools to facilitate their translation to the clinic.